DISEASES OF KIDNEYS
AND URINARY TRACT
Diseases of the kidneys are divided into 5 major groups:
1. Glomerular diseases.
2. Tubular diseases.
3. Interstitial diseases.
4. Vascular diseases.
5. Tumours of the kidney.
There are two main types of partial renal failure:
nephritic syndrome and nephrotic syndrome.
Nephritic syndrome is the result of disturbance of glomerular structure that involves reactive cellular proliferation. This causes reduced glomerular blood flow (leading to reduced urine output oliguria), leakage of red cells from damaged glomeruli (hematuria), and consequent retention of waste products (uremia). The low renal blood flow activates the renin-angiotensin system, with fluid retention and mild hypertension. Small amounts of proteins are also lost in the urine, but this is usually trivial. The hematuria is not gross and is usually manifested as a smoky brown discoloration of urine.
Nephrotic syndrome is the result of abnormality in glomerular basil membranes or mesangium, such that the glomerulus loses the capacity for selective retention of proteins in the blood. This leads to loss of very large amounts of protein, mostly albumin, in the urine (proteinuria), with consequent loss of protein from the blood (hypoalbuminemia) leading to edema. Other indications of renal abnormality are intermittent hematuria and persistent proteinuria which can be thought of as early partial renal failure. The latter may precede the development of a nephrotic syndrome.
ACUTE RENAL FAILURE
Acute renal failure is characterized by widespread abrupt cessation of nephron function. Acute renal failure is a form of total renal failure in which the majority ofnephrons suddenly and simultaneously stop working.
The causes of acute renal failure may be pre-renal (e.g., inadequate cardiac output and hypovolemia or vascular disease causing reduced perfusion of the kidney), intra-renal (e.g., rapidly progressive glomerulonephritis, acute tubular necrosis, pyelonephritis), post-renal (e.g., caused by a mass, within the lumen, or from wall of the tract, or from external compression).
Clinically this causes a dramatic fall in urine production (oliguria), which is often total (anuria). With little opportunity for metabolic compensation, problems of disturbed fluid and electrolyte balance and failure of elimination develop rapidly. There is an increase in serum potassium level and metabolic acidosis, and nitrogen retention with uremia. Several diseases can produce acute renal failure, all of which cause sudden generalized cessation of nephron activity.
CHRONIC RENAL FAILURE
Chronic renal failure is a form of total renal failure caused by progressive destruction of individual nephrons over a long period of time.
The disease leading to chronic renal failure can generally be classified into two major groups: those causing glomerular pathology, and those causing tubulo-interstitial pathology.
The important examples of chronic glomerular diseases causing chronic renal failure are primary and systemic. Primary glomerular pathology are chronic glomerulonephritis, lipoid nephrosis (minimal change disease) and anti-glomerular basement membrane nephritis. Major examples of systemic glomerular pathology are systemic lupus erythematosus, serum sickness nephritis and diabetic glomërulosclerosis.
Tubulointerstitial diseases can be classified according to initiating etiology into 4 groups: vascular (e.g., primary or essential hypertension), infectious (e.g., chronic pyelonephritis), toxic (e.g., intake of high doses of analgetics such as phenacetin, aspirin and acetaminophen) and obstructive (e.g., stones, blood clots, tumours, strictures).
As more and more nephrons are destroyed, renal function becomes progressively more impaired. However, in contrast to acute renal failure there is opportunity for metabolic compensation. The latter produces early inability to concentrate urine (polyuria) and abnormalities in biochemical homeostasis (including salt and water retention, compensated metabolic acidosis, and other electrolyte imbalances, particularly hyperkalemia). Sodium and fluid retention may cause hypertension.
In contrast to many cases of acute renal failure, chronic renal failure is not reversible because there has been destruction of nephrons. A kidney in which all nephrons have been irreversibly damaged is macroscopically small and shriveled and is known as an end-stage kidney.
GLOMERULONEPHRITIS
The term glomerulonephritis is traditionally used to describe the group of diseases in which the primary pathology is some sort of structural abnormality in the glomerulus. Despite the suffix <-itis>>, most are not characterized by inflammatory changes. Damage to the glomerulus may be severe, leading to permanent scarring, in which case the associated tubule atrophies. Alternatively, some conditions produce temporary abnormality and, following resolution, there is restoration of nephron function.
Principles of glomerulonephritis classification. Glomerulonephritis may be primary or secondary. According to the etiology it may be bacterial, viral, unclear. According to the pathogenesis there are 2 types of glomerulonephritis — immunoassociated and nonimmunoassociated. According to the course glomerulonephritis may be classified into acute, subacute, chronic. In morphological classification, topography, character, propagation of pathological process are accounted.
Glomerular disease is classified according to the histological pattern of damage seen on renal biopsy, hence a knowledge of this aspect of histopathology is needed to understand disease. This arrangement is supplemented by further classification according to etiology of disease.
Morphology. Five main patterns of response to damage are seen in the glomerulus, combinations of which describe all types of glomerular disease.
1. Proliferation of endothelial cells leads to occlusion of capillary lumina, often with neutrophils present. This proliferation reduces the flow through glomeruli and correlates with äliguria and uremia.
2. Proliferation of mesangial cells, which is usually associated with increased production of matrix, is a common feature of many glomerular diseases. In some cases this may regress once the acute episode is over, in others the production of excess mesangial matrix over many years eventually leads to clerosis
(hyalinization) of all or part of the glomerular tuft, with loss of capillary lumina.
3. Basement membrane thickening may be due to the deposition of an abnormal substance (immune complexes or amyloid), synthesis of new basement membrane material, insinuation of mesangial cytoplasm and matrix, or a combination of these causes.
4. Capillary wall necrosis, usually fibrinoid necrosis, occurs in diseases in which there is severe acute capillary wall damage, e.g. necrotizing vasculitis and accelerated (malignant) hypertension.
5. Crescent formation is an important reaction to severe glomerular capillary damage, stimulated by leakage of blood and fibrin into the urinary space. Crescents are formed by proliferation of the epithelial cells that line the Bowman’s capsule, which crush the glomerulus, and lead to permanent loss of the whole nepbron. The presence of widespread crescents is a poor prognostic sign, relating to severe and usually rapidly progressive disease.
Important types of glomerulonephritis
Acute diffuse proliferative glomerulonephritis
usually presents as the nephritic syndrome. Acute proliferative glomerulonephritis is a diffuse global disease of glomeruli caused by deposition of immune complexes in glomeruli, which is stimulated by a preceding infection. Although infection is most commonly streptococcal, a range of bacterial, viral and protozoal infections can also stimulate this pattern of disease.
Macroscopically, the kidneys are symmetrically enlarged, weighing one and a half to twice the normal weight. The cortical layer as well as sectioned surface show petechial hemorrhages giving the characteristic appearance of fleabitten kidney.
Microscopically, there is increased cellularity of the glomerulus, with four main features:
1. Proliferation of endothelial cells produces occlusion of capillary lumina, leading to reduced glomerular filtration, with rising blood pressure and blood levels of nitrogenous components (urea and creatinine).
2. Presence of immune complexes in lumps on the epithelial side.
3. Presence of neutrophil polymorphs in capillanes.
4. Mild mesangial cell proliferation. In diffuse acute proliferative glomerulonephritis there is endothelial proliferation with neutrophils, subepithelial lumpy immune-complex deposits, and mesangial cell increase. The glomenulus is hypercellular due to proliferation of endothelial and mesangial cells. Glomerular capillary lumina cannot be identified because they are obliterated by the proliferating endothelial cells. The immune-complex deposits can only be seen by electron microscopy.
Membranous nephropathy presents with proteinuna and the nephrotic syndrome.
The disease passes through three pathological stages:
1) Immune-complex deposited on epithelial side of basement membrane.
2) New basement membrane deposited around immune-complex deposits.
3) Immune-complex deposits disappear, leaving thickened basement membrane.
The abnormality of the basement membrane renders it unusually permeable; it no longer selectively retains proteins, leading to heavy proteinuria and the nephrotic syndrome. With time, the abnormal glomeruIi develop increase in mesangial matrix produced by the mesangial cells. This, together with membrane thickening, causes gradual hyalinizatioñ of the glomeruli and death of individual nephrons. This process takes place over many years and, from a nephrotic syndrome, the patient may develop chronic renal failure with uremia.
Complications: rapidly progressive and chronic glomerulonephritis, uremia, chronic renal failure.
Diffuse membranoproliferative glomerulonephritis often presents as a nephrotic or a mixed nephritic and nephrotic syndrome. Membranoproliferative glomerulonephritis (MPGN), also called mesangiocapillary glomerulonephritis, is a pattern of glomerular reaction to complement abnormalities. Some are secondary to systemic disorders.
Macroscopically, the kidneys are pale in appearance and firm in consistency.
Microscopically, as the name implies, the common factors in this process are mesangial proliferation and basement membrane thickening as the main structural abnormalities. The basement membrane abnormality is responsible for the clinical symptoms of proteinuria or a full nephrotic syndrome. Because there is cellular proliferation, patients may also develop hematuria or a nephritic syndrome. A mixed nephrotic and nephritic syndrome is seen in some cases.
Focal segmental proliferative glomerulonephritis can be either primary or secondary.
In almost every case, focal glomerulonephritis is also <<segmental>>, only occasional lobules of the glomemlar tuft being involved in disease. In this type of reaction, there is cellular proliferation affecting only one segment of the glomerular tuft and occurring in only a proportion of all glomenili. As there is cellular proliferation, patients tend to present with hematuria or the nephritic syndrome with proteinuria. In some cases the focal glomerulonephritis can be a stimulus for crescent formation.
Chronic glomerulonephritis. The term (<chronic glomerulonephritis>> is used when a patient has chronic renal failure with small contracted kidneys in which all the glomeruli are hyalinised. Because renal glomeruli are destroyed, it is ofteot possible to ascertain the cause.
The conditions which may progress to chronic glomerulonephritis, in descending order of frequency, are rapidly progressive glomerulonephritis, membranous glomerulonephritis, membranoprolifèrative gbmerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, acute post-streptococcal glomerulonephritis.
Morphology. Macroscopically, the kidneys are usually small and contracted weighing as low as
glomeruli are reduced iumber and most of those present show completely hyalinised tufts, giving the appearance of acellular, eosinophilic masses which are PAS-positive. Many tubules completely disappear and there may be atrophy of tubules close to scarred glomeruli. Tubular cells show hyalin-droplet degeneration and tubular lumina frequently contain eosinophilic, homogeneous casts. There is fine and delicate fibrosis of the interstitial tissue and varying number of chronic inflammatory cells are often seen. Advanced cases which are frequently associated with hypertension show conspicuous arterial and arteriolar sclerosis.
Diseases of pre-glomerular vessels, or central pump failure, have a major impact on the function of the kidney.
In general, slowly progressive disease of the vessels leads to slowly progressive destruction of nephrons, ischemic glomerular filtration failure and ischemic tubular atrophy, culminating in chronic renal failure and a small, shrunken end-stage kidney.
ischemia of the affected kidney, with reduction in function of all nephrons on that side, producing an end-stage shrunken kidney. The unaffected kidney undergoes compensatory hypertrophy, so renal function is largely unaffected in most cases Renal artery stenosis is also caused by arterial fibromuscular dysplasia.
3. The kidney is frequently affected in diabetes mellitus.
Diabetes causes increased severity of atherosclerosis in large, medium and small arteries, predisposing to renal ischaemia. ifi addition, diabetes causes hyaline arterioloscierosis in afferent arterioles, resulting in ischemic glomerular damage.
Diabetic glomerular damage involves diffuse thickening of the glomerular capillary basement membrane, leading to an increase in permeability, proteinuria and, occasionally, the nephrotic syndrome.
Nephrotic Syndrome: Pathophysiology
Nephrotic syndrome may be induced by noninflammatory or inflammatory (glomerulonephritis conditions. The resultant damage, which may be subtle, produces increased permeability of the glomerular capillaries leading to proteinuria. Clinically, nephrotic syndrome is characterized by proteinuria in excess of 3.5 g/d/1.73 nr body surface area, edema, hypoalbuminemia, and hyperlipidemia. Prolonged massive proteinuria and resultant hypoprotein-emia are the common denominators for all consequent metabolic and nutritional defects. Glomerular inflammation also may lead to a decrease in renal blood flow, which may activate the reninangiotensin system, increasing production of angiotensin II and causing hypertension.
Nephrotic Syndrome: Pathology
A spectrum of glomerular lesions can produce nephrotic syndrome. Minimal change disease (lipoid nephrosis) shows little or no change by light microscopy. Fused epithelial foot processes and occasional immunoglobulin (Ig) M deposits are seen by electron microscopy. If the disease is complicated by focal and segmental sclerosis, fused epithelial foot processes, capillary collapse, or mesangial expansion with “/-globulin deposits, response to immunosuppressive therapy deteriorates. Membranous nephropathy is characterized by thickened capillary walls, spikes in the basement
membrane due to antigen-antibody complexes beneath the epithelial cells (membranous disease), and diffuse granular deposits of IgG and C5 (complement). Mesangioproliferative glomerulonephritis shows thickening of glomerular capillary walls complicated by mesangial proliferation and sclerosis with subendothelial deposits of C( and IgG in a lumpy, nonlinear pattern. Focal segmental inflammatory necrosis and crescent formation signals a poor response to immunosuppressive therapy.
DISEASE OF RENAL TUBULES
AND INTERSTITIUM
Disease of the renal tubules and interstitium accounts for a large number of cases of renal failure. The main causes of disease are infections, ischemia, and toxic and metabolic disorders.
Acute pyelonephritis is caused by bacterial infection with organisms entering the kidney by two routes. Ascending infection from the lower urinary tract is most common. Predisposing factors that lead to ascending urinary tract infection are pregnancy, diabetes mellitus, stasis of urine, structural defects of the urinary tract, and reflux of urine from bladder into ureters (vesicoureteric reflux). Bloodstream spread in bacteremic or septicemic states (unusual). Although less common, this seems to be the most likely cause in elderly patients who develop pyrexia of unknown origin, often with rigors, and acute renal failure.
Macroscopically, the kidneys show variable numbers of small, yellowish white cortical abscesses, which are usually spherical, under
Complications: papillary necrosis, pyonephrosis, perinephric abscess.
Chronic pyelonephritis is characterized by chronic interstitial inflammation associated with large scars of the kidney.
Chronic pyelonephritis is a common cause of end- stage chronic renal failure, accounting for about 15% of all cases. The disease is characterized by interstitial chronic inflammation and scarring, which destroys nephrons. The areas of scarring are associated with distortion of the pelvicalyceal system of the kidney. Renal-induced hypertension may develop and hypertensive-induced vascular damage can increase renal damage.
There are two forms of chronic pyelonephritis:
reflux-associated and obstructive. In the most common form, reflux-associated chronic pyelonephritis, reflux of urine from the bladder up the ureters predisposes to recurrent bouts of inflammation, leading to scarring. This occurs in childhood, and disease becomes manifest in early adult life, with progressive impairment of.
In obstructive chronic pyelonephritis, recurrent episodes of infection occur in a kidney in which there is obstruction to the pelvicalyceal drainage. The obstruction, which can be at any level in the lower urinary tract, may be due either to anatomical abnormality or to renal tract stone.
Kidneys have irregular areas of scarring, seen as depressed areas, 1—2 cm in size. The scars are sited over a clubshaped distorted renal calyx and are associated with fibrous scarring of the renal papilla. The most common site for these areas of scarring is the renal calyces at the poles of the kidney.
Histologically the kidney has irregular areas of interstitial fibrosis with chronic inflammatory cell infiltration. Tubules are atrophic or maybe dilated and contain proteinaceous material. Glomeruli show periglomerular fibrosis and many demonstrate complete hyalinization.
Acute tubular necrosis is a common and important cause of reversible acute renal failure. In acute tubular necrosis, metabolic or toxic disturbances cause necrosis of renal tubular epithelial cells. Although the tubular epithelial cells die and are shed, regeneration is possible if the damaging stimulus is corrected, since residual viable tubular epithelial cells can proliferate to re-populate the tubules. It is this regenerative capacity of the tubular epithelial cells that permits adequate tubular functioning after renal transplantation following a prolonged period of hypoxia of the graft.
There are three phases to acute tubular necrosis:
1. Oliguric phase. A damaging stimulus causes necrosis of renal tubular epithelium. There is blockage of renal tubules by necrotic cells, and a secondary reduction in glomerular blood flow (caused by arteriolar constriction) reduces glomerular filtration. Macroscopically, kidneys are diffusely swollen and edematous. Patients develop acute renal failure and1 oliguria. Suppol-tive measures are required to preven hyperkalemia and fluid overload.
2. Polyuric phase. Over 1—3 weeks, regeneration of renal tubular epithelium takes place, with remova
of dead material by phagocytic cells, as well as in the form of casts in urine. As tubules open up and glomerular blood flow increases, patients develop polyuria. This is because the regenerated tubular cells are undifferentiated and have not developed the specializations necessary forresorption of electrolytes and water. Replacement of fluid and electrolytes is needed to compensate for excessive loss from urine.
3. Recovery phase. Tubular cells re-establish differentiation and there is restoration of renal function.
Mácroscopically, in acute tubular necrosis, kidneys are severely swollen. Microscopically, the lining epithelial cells of the tubules are dead and the tubular lumen are filled with necrotic cell debris.
TUMOURS OF THE KIDNEYS
Benign tumours of the kidney are frequent incidental findings: renal adenomas, renal oncocytomas, angiomyolipomas are tumours composed of smooth muscle, fat, and large blood vessels. Renal tibromas are very common small benign tumours of spindle cells.
Adenoma. Traditionally, this tumor has been defined as a renal epithelial neoplasm that is less than
Angiomyolipoma is a benign tumor composed of a mixture of fat, blood vessels, and smooth muscle tissue. These tumors are of significance because clinically and radiologically they often are misdiagnosed as carcinomas. Macroscopically angiomyolipomas range in size from a few centimeters in diameter to quite large. They affect the cortex and medulla equally and have no predilection for the right or left kidney. On cut surface, they exhibit a yellow- to-gray color, depending on fat content. Microscopically there is an admixture of mature adipose tissue, thick-walled vessels, and varying amounts of smooth muscle tissue.
Mesoblastic nephroma (benign nephroblastoma) is a congenital hamartoma that commonly is confUsed with Wilms’ tumor. Most mesoblastic nephromas are diagnosed in the early months of life. Macroscopically mesoblastic nephromas vary in size and are unilateral. On cut section, they have a characteristic firm, whitish surface that resembles smooth muscle. Necrosis usually is absent, butcystic changes may be present. The tumors lack clear encapsulation. Microscopically. the predominant features are interlacing bundles of mature connective tissue, which entrap the glomeruli. and other renal elements. Rarely, foci of dysplastic cartilage and embryonic mesenchyme may be present.
Renal adenocarcinoma is the most common malignant tumour of the kidney.
Renal cell carcinoma (hypernephroma) is an adenocarcinoma that arises from the proximal or distal convoluted tubule.
Etiology and pathogenesis. The cause of these tumors remains obscure, but they have been produced in laboratory animals using chemical, physical, and viral agents. The chemicals used include aromatic hydrocarbons, amines, amides, and such aliphatic compounds as aflatoxins (metabolic products of the fungus). Partial deletion of the short arm chromosome 3 is a frequent cytogenetic finding in renal cell carcinoma.
Pathology Renal cell carcinoma may affect either kidney and has no predilection for a specific location within the organ. Macroscopically the tumor protrudes from the renal cortex as an irregular bosselated.mass, which, on cut section, has a characteristic yellow- orange appearance. Hemorrhage and necrosis are commonly seen. At the periphery of the tumor, the normal parenchyma is compressed, forming a pseudocapsule. Foci of myxoid degeneration and calcification may be present. Microscopiccally several patterns can be seen, including papillary, tubular, granular, solid, or sarcomatoid. Most tumors are composed of clear cells with distinct cytoplasmic membranes, abundant cytoplasm, and eccentric nuclei. The lesions are markedly vascularized, with little stroma between the cells; occasionally clusters of histiocytes and inflammatory cells are present. Renal cell tumors frequently show areas of pleomorphism and giant cells and, thus, resemble different types of sarcomas.
Renal-cell carcinoma metastasizes mainly through the bloodstream and lymphatic spread also is possible.
Nephroblastoma (Wilmy’ tumour) is an embryonal tumour derived from the primitive metanephros. Wilms’ tumor (nephroblastoma) is a mixed neoplasm composed of metanephric blastema and its stromal and epithelial derivatives at variable stages of differentiation. Wilms’ tumor is the most common malignancy of renal origin in children.
Etiology and pathogenesis. Very recent work has located a tumor suppressor gene on chromosome lipl3. Thought to repress transcription and designated WT-l, this gene is lost or deleted in sporadic and hereditary Wilms’ tumor. Nephroblastomas may be combined with several other congenital malformations, such as sporadic aniridia, microcephaly, mental retardation, and spina bifida.
Pathology. Wilms’ tumor can be unilateral, bilateral, or multifocal in its involvement of the same kidney. Macroscopically the tumors are large, well delineated, and well encapsulated. On cut section, they often appear grayish-white, with areas of hemorrhage and occasional cystic changes. The junction between the tumor and the kidney is sharp, often with a rim of normal kidney parenchyma. Microscopically the lesions are characterized by formation of abortive or embryonic glomerular and tubular structures surrounded by an immature spindle cell stroma. The epithelial elements may be scanty or predominantly tubular. The stroma may show different elements, such as skeletal muscle, cartilage, and fat.
Frequent metastasis of the tumor are lymphogenic and hematogenic. The renal hilar and paraaortic lymph nodes are involved. The lungs, liver, adrenal glands, diaphragm, retroperitoneum, and bones also are commonly involved.
DISEASES OF TUE LOWER URINARY TRACT
There are five main groups of disorders in the lower urinary tract: infection, which is often secondary to stasis of urine, following obstruction to flow; obstruction by intrinsic occlusion or extrinsic pressure; stone formation, which is often secondary to stasis of urine combined with infection; tumour formation, i.e. neoplasia of transitional-cell epithelium; developmental abnormalities.
Infection
Cystitis
Cystitis results from an inflammation of the urinary bladder. Cystitis usually is a self-limited condition or one easily treated with antibiotics. In some circumstances, such as poorly controlled DM or chronic urinary tract obstruction, cystitis is a severe condition that progresses to involve the upper urinary tract and kidneys and leads to renal failure. In adult women, cystitis is usually limited to the trigone and rarely develops into a severe ulcerative or hemorrhagic disease. In adult men and in children of both sexes, cystitis usually signifies the presence of an underlying anatomical or physiologic abnormality. On cystoscopy, various patterns of involvement may be seen, including cystitis cystica, which is manifest as multiple epithelial-lined cysts. The chief complication of cystitis is spread of infection to the kidneys.
Infections in the lower urinary tract are predisposed by obstruction and stasis. Lower urinary tract infection is usually due to Gram-negative coliform bacilli, e.g. E. coli and Proteus, which are normally commensals in the large bowel; because they have a short urethra, women are particularly prone to developing ascending infections. In men, lower urinary tract infection is usually associated with structural abnormalities of the lower urinary tract and stasis due to obstruction. Diabetes mellitus also predisposes to infection.
Morphology. The pelvicalyceal system is dark reddish brown as a result of acute inflammation of the usually smooth creamy mucosal lining due to bacterial infection. The kidney is also congested and some small scattered abscesses are present in the cortex and medulla (acute pyelonephritis). Obstruction of the drainage of urine from the kidney causes hydronephrosis. Obstruction, one of the most important consequences of disease of the lower urinary tract, may occur at any place in the tract: renal pelvis (calculi, tumours), pelviureteric junction (stricture, calculi, extrinsic compression), ureter (calculi, extrinsic compression-pregnancy, tumour, fibrosis), bladder (tumour, calculi), urethra (prostatic hyperplasia or carcinoma, urethral valves, urethral stricture).
If obstruction occurs in the urethra, the bladder develops dilatation and secondary hypertrophy of muscle in its wall. This predisposes to development of outpouching of the bladder mucosa (diverticulae).
If obstruction occurs in a ureter, there is dilatation of the ureter (megaureter), with progressive dilatation of the renal pelvicalyceal system, termed hydronephrosis. Fluid entering the collecting ducts cannot empty into the renal pelvis and there is intrarenal resorption of fluid. At this stage, if the obstruction is relieved, renal function returns to normal. However, if obstruction persists, there is atrophy of renal tubules, glomerular hyalinization, and fibrosis. As an end-stage, the renal parenchyma becomes severely atrophic and renal fimction is pennanently impaired.
Urinary tract obstruction also predisposes to infection and stone formation.
Urinary calculi
Urinary calculi may form anywhere in the lower urinary tract (urolithiasis), the most common sites being the pelvicalyceal system and bladder. The two main predisposing factors for stone formation are increased concentration of solute in urine (low fluid throughput or primary increase in metabolite), and reduced solubility of solute in urine (due to persistently abnormal urinary pH). Conditions that cause these factors to operate are low fluid intake, urine stasis, persistent urinary tract infection, and primary metabolic disturbances.
The most common urinary stones, accounting for 80% of cases, are composed of calcium oxalate or phosphate. Half of these cases are associated with idiopathic hypercalciuria, with only about 10% being caused by hypercalcemia. Other cases may be caused by hyperoxaluria, which has several associations, e.g. inflammatory bowel disease. The second most common type of calculi, accounting for 15% of cases, are those composed of magnesium, ammonium, and calcium phosphates (struvite). They are associated with infection in the lower urinary tract as a result of urea- splitting organisms, which make urine permanently alkaline
Uric acid stones account for about 5% of cases and are predisposed by conditions causing hyperuricaemia, e.g. gout. However, 50% of patients with uric acid stones do not have hyperuricemia, and it is suggested that production of persistently acid urine is the predisposing factor. Cystine stones are rare, accounting for under 1% of cases. They are seen in heritable tubular transport defects causing cystinuria.
The renal pelvis is filled with a large calculus that is shaped to its contours, resembling the horn of a stag. The calyceal system at the lower pole contains separate rounded calculi.
Pyelonephritis
Pyelonephritis, an infectious disease of the kidney, is usually induced by pyogenic microorganisms, particularly Escherichia coli and other gram-negative bacteria. The primary process is inflammation of the renal interstitium and the tubules. In acute pyelonephritis, the swollen kidney exhibits multiple small abscesses seen as linear, yellowish areas radiating continuously from the corticomedullary junction to the surface and sometimes extending through the medulla into the papillae. Microscopically, the yellow lesions correspond to a heavy interstitial infiltrate of polymorphonuclear leukocytes, with pus formation and liquefactioecrosis. The lesions are generally patchy with preserved glomeruli and vessels. The characteristic gross feature of chronic pyelonephritis is a coarsely granular contracted kidney with significant loss of renal parenchyma in the cortex and the medulla. Chronic interstitial inflammation (lymphocytes, macrophages) is widespread; many tubules are destroyed, and those remaining are dilated, lined by flattened epithelium, and filled with proteinaceous casts.
CYSTIC DISEASE OF THE KIDNEY
There are several cystic diseases of the kidney, some of which produce renal failure by causing disturbance of renal structure. Importantly, some conditions are heritable.
Adult polycystic disease is inherited in an autosomal dominant trait, generally becoming clinically manifest in adult life. Increasingly, disease is detected in childhood, with family screening and ultrasound examination. Cysts develop and progressively enlarge over a number of years, but remain asymptomatic until the number and size of the cysts is so great that the patient becomes aware of abdominal masses. At about the same time, the replacement and compression of functioning renal parenchyma by the cysts leads to slowly progressive impairment of renal function, and patients develop chronic renal failure and hypertension. Patients with adult-type polycystic renal disease may also develop cysts in the liver, lung and pancreas. There is an association with berry aneurysms of the cerebral arteries which, with development of hypertension, predisposes to intracranial hemorrhage.
Urinary Tract Calculi
Clinically significant complications of urinary calculi involve up to 10% of the population. The calculi affect men more than women, with peak occurrence between 20 and 50 years of age. The etiology is poorly defined, although factors leading to highly concentrated urine predispose to stone formation. Most stones originate in the kidney and are composed of calcium oxylate and other calcium salts embedded in an organic matrix. Certain metabolic diseases (hyperoxaluria and disorders of amino acid metabolism) predispose to stone formation. Renal calculi may remain in the pelvis of the kidney (staghorn calculus) or pass down the ureter, which produces the severe pain of renal colic. Destruction of renal parenchyma may result from progressive growth of the calculus, obstruction, or infections. Occasionally, calculi form in the ureter or urinary bladder as a result of urinary stasis secondary to various congenital or acquired anomalies.
Adult polycystic kidney disease has an autosomal dominant inheritance pattern, with individual cases resulting from a mutation of the PKD1 gene on chromosome 16, the PKD2 gene on chromosome 4, or a yet-to-be-localized PKD3 gene. In contrast, infantile or childhood polycystic disease has an autosomal recessive inheritance pattern and represents a severe form of renal dysplasia. Adult polycystic kidney disease is relatively common, occurring in 1 of 400 to 1000 live births and accounting for approximately 10% of chronic renal failure in adults. Kidney damage is a slowly developing but
progressive process that eventually reaches clinical significance in all affected individuals surviving into the ninth decade of life. In the more advanced stages, destruction of renal tissue results in azotemia and physical discomfort from the sheer size of the large cystic masses. Hypertension occurs frequently, as do urinary tract infections. Associated conditions include intracranial berry aneurysms. The patients inevitably become dependent on hemodialysis and are candidates for kidney transplantation.
Benign Renal Tumors
Benign tumors of the kidney may mimic malignant tumors and should be considered in the differential diagnosis of a renal cyst. Renal adenomas are typically small cortical nodules, which often grow within small cysts. They are usually papillomatous structures but may have a tubular or alveolar growth pattern. Occasionally, a large, single adenoma is found. The cells of adenomas are usually cuboidal and show well-differentiated cytology and growth pattern.
The adenoma should be considered premalignant and prone to give rise to clones of malignant cells. Tumors larger than
Infantile polycystic disease is uncommon and is encountered at birth. Children develop severe renal failure, with compression of the lungs due to massive enlargement of the kidneys. Simple renal cysts are the most common form of renal cystic disease and must be distinguished from the congenital types discussed above. They are widely held to be acquired abnormalities, incidence increasing with age. They contain clear, watery fluid and have a smooth lining. Simple cysts may be single or multiple and vary in size, generally being no larger than 5—6 cm. They have no effect on renal function, but may rarely become infected or develop haemorrhage.
Acquired cystic disease is seen in kidneys left in situ while patients are treated by dialysis or transplantation for chronic renal failure. The kidney is converted into a mass of large cysts. Hemorrhage into cysts is common, leading to bloodstained contents.
DISEASES OF THE REPRODUCTIVE
SYSTEM
DISEASES OF THE PROSTATE
Prostatitis is inflammation of the prostate. Prostatitis may be acute, chronic and granulomatous types.
Acute prostatitis. Acute focal or diffuse suppurative inflammation of the prostate is not uncommon. It occurs most commonly due to ascent of bacteria from the urethra, less often by descent from the upper urinary tract or bladder, and occasionally by lymphogenous or hematogenous spread from a distant focus of infection. The infection may occur spontaneously or may be a complication of urethral manipulation such as by catheterisation, cystoscopy, etc. The common pathogens are E. coli, and others such as Kiebsiella, Proteus, Pseudomonas, Enterobacter gonococci, staphylococci and streptococci.
Morphology. Macroscopically, the prostate is enlarged, swollen and tense. Cut section shows multiple abscesses and foci of necrosis. Microscopically, the prostatic acini are dilated and filled with neutrophilic exudate. There may be diffuse acute
inflammatory infiltrate. Edema, hyperemia and foci of necrosis frequently accompany acute inflammatory involvement.
Chronic prostatitis. Chronic prostatitis is more common and foci of chronic inflammation are frequently present in the prostate of men above 40 years of age. Chronic prostatitis is usually asymptomatic but may cause allergic reactions, iritis, neuritis or arthritis. Chronic prostatitis is of 2 types — bacterial and abacterial.
Chronic bacterial prostatitis is caused in much the same way and by the same organisms as the acute prostatitis.
Chronic abacterial prostatitis is more common these days. Prostatic secretions is always negative, though leucocytosis is demonstrable in prostatic secretions. The pathogens implicated are Chlamydia trachomatis and Ureaplasma urealyticum.
Morphology. Macroscopically, the prostate may be enlarged, fibrosed and shrunken. Microscopically, the diagnosis of chronic prostatitis is made by foci of lymphocytes, plasma cells, macrophages and neutrophils within the prostatic substance. Prostatic calculi and foci of squamous metaplasia in the prostatic acini may accompany inflammatory changes.
Granulomatous prostatitis. Granulothatous prostatitis is a variety of chronic prostatitis, probably caused by leakage ofprostatic secretions into the tissue, or could be of autoimmune origin. Morphology. Macroscopically, the gland is firm to hard, giving the clinical impression of psoriatic carcinoma on rectal examination. Microscopically, the inflammatory reaction consists of macrophages, lymphocytes, plasma cells and some multinucleated giant cells.
Nodular hyperplasia. Non-neoplastic tumour– like enlargement of the prostate, commonly termed benigodular hyperplasia or benign enlargement of prostate, is a very common condition in men. It becomes increasingly more frequent above the age of 50 years and its incidence approaches 75—80 % in men above 80 years.
The cause of benigodular hyperplasia has not been fully established. A few etiologic factors such as endocrinologic, racial, inflammation and arteriosclerosis have been implicated but endocrine basis for hyperplasia has been more fully investigated and considered a strong possibility in its genesis. It has been found that both sexes elaborate androgen and estrogen, though the level of androgen is high in males and that of estrogen is high in females. With advancing age, there is decline in the level of androgen and a corresponding rise of estrogen in the males. The periurethral inner prostate which is primarily involved in benigodular hyperplasia is responsive to the rising level of estrogen, whereas the outer prostate
which is mainly involved in the carcinoma is responsive to androgen.
Morphology. Macroscopically, the enlarged prostate is nodular, smooth and firm and weighs 2—4 times its normal weight i.e. may weigh up to 40—
Microscopically, in every case, there is hyperplasia of all three tissue elements in varying proportions — glandular, fibrous and muscular.
Glandular hyperplasia predominates in most cases and is identified by exaggerated intra-acinar papillary infoldlngs with delicate fibrovascular cores. The lining epithelium is two-layered: the inner call columnar mucus-secreting with poorly-defined borders, and the outer cuboidal to flattened epithelium with basal nuclei.
Fibromuscular hyperplasia when present as dominant component appears as aggregates of spindle cells forming an appearance akin to fibromyoma of the uterus.
Carcinoma ofprostate. Cancer of the prostate is the second most common form of cancer in males, followed in frequency by lung cancer. It is a disease of men above the age of 50 years and its prevaknce increases with increasing age so that 60% or more of men 80 years old have asympto-matic carcinoma of the prostate. There are following types carcinoma of the prostate.
Latent carcinoma. This is found unexpectedly as
a small focus of carcinoma in the prostate during
autopsy studies in men dying of other causes. Its
incidence in autopsies has been variously reported as
25—35%.
Occult carcinoma. This is the type in which the patient has no symptoms of prostatic carcinoma but shows evidence of metastases on clinical examination and investigations.
Clinical carcinoma. Clinical prostatic carcinoma is the type detected by rectal examination and other investigations and confirmed by pathologic examination of biopsy of the prostate.
Nodular prostatic hyperplasia has been suggested by some as precursor for development ofprostatic cancer.
Morphology. Macroscopically, the prostate may be enlarged, normal in size or smaller than normal. In
95% of cases, prostatic carcinoma is located in the peripheral zone, especially in the posterior lobe. The malignant prostate is firm and fibrous. Cut section is homogeneous and contains irregular yellowish areas.
Microscopically, there are 4 histologic types of cancer of the prostate adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma and undifferentiated carcinoma.
DISEASES OF THE ENDOMETRIUM
Endometrial hyperplasia is caused by estrogenic stimulation and may be pre-neoplastic. An endogenous response may be seen with successive anovulatory cycles or estrogen-secreting tumours, and an exogenous response with estrogen-containing drugs. The importance of endometrial hyperplasia is that it is associated with an increased risk of development of adenocarcinoma of the endometrium.
There are several histological types — simple hyperplasia — being the most common pattern, diffUsely affecting the whole endometrium. Proliferation of glands can be seen, with evident mitoses and stratification of cells. Glands grow in a regular tubular pattern, but are often dilated however, there is no cytological atypia of the nuclei. This type is associated with a very slightly increased risk of malignancy after a long period of time, typically over 10 years. Complex hyperplasia is almost always seen focally within the endometrium. There is obvious proliferation of epithelium, evident by mitotic figures, but the glands grow in an irregular pattern, with branched irregular contours and little intervening stroma. The cells forming the glands do not show cytological atypia. This type is associated with a slightly increased risk of development of malignancy. Complex atypical hyperplasia is commonly seen only focally within the endometrium. Like complex hyperplasia, there is proliferation of epithelium, evident by mitotic figures, and the glands grow in an irregular pattern, with branched irregular contours However, the cells forming the glands show cytological atypia, with pleomorphism and hyperchromatism. About 30% of cases with this pattern of hyperplasia will develop a carcinoma of the endometrium, usually within 5 years of diagnosis.
A cute endometritis is usually encountered as a complication of pregnancy.
Chronic endometritis is usually associated with recent gestation, pelvic inflammatory disease. Chronic endometritis may be associated with menstrual irregularities, but is also found in women who are being investigated for infertility. Histologically the endo metrium shows lymphoid infiltration, with formatioll of plasma cells. The majority of cases are associated with a definite clinical risk factor for developin
inflammation. The condition has occurred after recent pregnancy, miscarriage or instrumentation in 50% of cases, in association with pelvic inflammatory disease (e.g. salpingitis) in 25% of cases. In the remaining 5% of cases without a defined risk factor, chronic endometritis may be caused by gonococcal or chlamydial infection, or tuberculosis.
In tuberculous endometritis, because granulomas form only in secretory endometrium, they may not be seen in samples taken from early in the cycle. The condition is commonly part of more widespread infection involving fallopian tubes.
Endometrial polyps are localized overgrowths of endometrial glands and stroma. Endometrial polyps are very common and are usually seen in the pen- menopausal age range. They are thought to be caused by over-proliferation of glands in response to estrogenic stimuli.
Macroscopically they vary in size but are usually 1—3 cm in diameter and are usually sited in the uterine hindus. They appear as firm smooth nodules within the endometrial cavity occasionally prolapsing through the cervical ostium.
Microscopically, they are made up of cystically dilated endometrial glands in a vascular stroma. They are clinically associated with menstrual abnormalities and dysmenorrhea, but may develop ulceration or undergo torsion. Endometriosis. Endometriosis is a condition in which ectopic endometrium develops outside the uterine cavity. It affects 7% women of reproductive age, with associated infertility in about 30% of cases. The common sites for ectopic endometrial growth are ovaries, fallopian tubes, round ligaments, and pelvic peritoneum. Less common sites are intestinal wall, bladder, umbilicus, and laparotomy scars. Rarely, involvement of lymph nodes, lung and pleura is seen. The ectopic endome-trium still responds to cyclical hormonal stimulation, with phases of proliferation and breakdown with bleeding. The bleeding and breakdown stimulate the formation of fibrous adhesions and accumulation of hemosiderin pigment.
Macroscopically, foci of endometriosis appear as cystic and solid masses, which are characteristically dark brown from iron pigment accumulated as a result of repeated bleeding. Microscopically, endometrial glands and stroma are seen, together with fibrosis and macrophages containing iron pigment.
Complications; endometrial tissue growing in abnormal sites stimulates fibrosis and may cause fibrous adhesions between adjacent organs. When peritoneum is involved, adhesions may cause bowel obstruction. The condition usually presents with cyclical pelvic pain, dysmenorrhea, and infertility. When it affects the fallopian tubes and ovaries, the whole of the fallopian tube and ovary may be converted
to a cystic mass containing brown, semi-liquid material (chocolate cyst).
Endometrial carcinoma. Carcinoma of the endometrium has become more common than the invasive carcinoma of the cervix in women. Whereas the decline in the incidence of cervical cancer is due to early detection and cure of in situ stage, increased frequency of endometrial carcinoma may be due to longevity of women’s life to develop this cancer of older females. The peak incidence at onset is 6th to 7th decades of life and is rare below the age of 40 years.
The exact etiology of endometrial cancer remains unknown. However, a few factors associated with increased frequency of its development are estrogen excess, obesity, diabetes, hypertension and nulliparous state.
Morphology. Macroscopically, endometrial carcinoma may have 2 patterns-localized polypoid tumour or a diffuse tumour, the latter being more common. The tumour protrudes into the endometrial cavity as irregular, friable and grey-tan mass. Extension of the growth into myometrium may be identified by the presence of soft, friable and granular tissue in cUt section. In advanced disease, the involvement may extend beyond the physiologic limits into the cervical canal, into the peritoneum, besides lymphatic metastases and hematogenous metastases to distant sites such as lungs, liver, bones and other organs.
Microscopically, most endometrial carcinomas are adenocarcinomas. Depending upon the pattern of glands and individual cell changes, these may be welldifferentiated, moderately-differentiated or poorly- differentiated.
Uncommon histologic variants of endometrial carcinoma are: adenocarcinoma with squamous metaplasia (adenocanthoma), adenosquamous carcinoma (when both components are frankly malignant), clear cell carcinoma, mucinous adenocarcinoma and
papillary serous carcinoma.
DISEASES OF THE CERVIX
The cervix is an important site of pathology, particularly in women of reproductive age. The ectocervix is covered by squamous epithelium, and the endocervical canal by mucus-secreting columnar epithelium, which shows glandular downgrowth. At various stages in a woman’s reproductive life, the junction between the squamous and columnar epithelium migrates onto the convexity •of the ectocervix, then back into the endocervical canal. This squamocolumnar junction is the seat of most of the epithelial diseases that occur in the cervix.
The original squamocolumnar junction is usually located in the region of the external os, but its precise location at birth is influenced by exposure to maternal hormones in utero.
Around puberty, hormonal influences cause extension of the columnar epithelium onto the ectocervix, forming an ectropion or cervical erosion. This process is augmented by a first pregnancy, particularly when it occurs shortly after menarche. Exposure of the sensitive columnar epithelium of the ectropion to the post-pubertal acidic environment of the vagina induces squamous metaplasia and a transformation zone between the endocervical columnar epithelium and the ectocervical squamous epithelium. This zone is composed of new squamous epithelium in an area previously occupied by columnar epithelium.
Thus the squamocolumnar junction is of variable size, but its site always approximates to the external Os. In older women it may retreat into the endocervical canal.
Squamous cell carcinoma of the cervix
The common presenting symptom is vaginal bleeding in the early stages, but advanced neglected tumours may cause urinary obstruction due to bladder involvement.
The histological type of the tumour is less important for prognosis than is the staging at diagnosis. Microinvasive carcinomas show minute foci of very superficial invasion, only detected histologically, and have a very good prognosis after local excision. Invasive carcinomas are staged according to the degree of local invasion, and survival is related to stage. Invasion of paracervical and external iliac nodes occurs early.
Invasive carcinoma of the cervix is most commonly squamous-cell carcinoma. Invasive carcinoma of the cervix may occur at any time during the reproductive and post-menopausal years, but the average age of development is about 50 years. It accounts for 3—5% of cases of carcinoma in females.
Macroscopically, early lesions appear as areas of. granular irregularity of the cervical epithelium, progressive invasion of the stroma causing abnormal hardness of the cervix. Late lesions appear as, ifingating, ulcerated areas, which destroy the cervix.
The vast majority of carcinomas of the cervix areS. squamous-cell carcinomas, arising from the transformation zone or ectocervix. Lesions fall into three histological patterns: keratinising squamous cell. carcinoma, non-keratinising large-cell squamous carcinoma, and non-keratinising small-cell squamous! carcinoma.
Non-neoplastic cystic lesions in ovaries are
DISEASES OF THE OVARIES
extremely common, the majority arising fron development of Graafian follicles, others being derived
From surface epithelium. Among the main types are mesothelial-lined inclusion cysts, which are small lesions ranging from microscopic up to 3-
Follicular cysts are derived from ovarian follicles and are lined by granulosa cells, with an outer coat of thecal cells. Cysts are, by definition, over
Corpus tuteutn cysts are caused by failure of
involution of the corpus luteum. Cysts are typically
2—3 cm in diameter, with a thick, yellow lining of
luteinized granulosa cells. There is continued
production of progesterone, resulting in menstrual
i regularity.
Theca-lutein cysts are usually seen as multiple bilateral cysts, up to
Polycystic ovary syndrome (Stein-Leventhal syndrome) is a common cause of infertility.
Patients are obese, hirsute, and have acne and menstrual abnormalities (amenorrhea or irregular periods). The ovaries show thickening of the capsule, and multiple follicular cysts with stromal hyperplasia. The pathogenesis of this syndrome is still
1. Endocervical differentiation: mucinous ovarian
uncertain. Patients have a persistent anovulatory state, high levels of estrogen, low levels of FSH with high levels of circulating androgen produced by the ovary. There is insulin resistance and hyperinsulinism. The high estrogen levels may cause endometrial hyperplasia and increase the risk of development of endometrial carcinoma.
It is not uncommon to see luteinizing hormone- driven ovarian hyperandrogenism, acne, anovulation, oligomenorrhea, and large, multifollicular ovaries in early to mid-puberty, arising as a self-limited maturational stage in development. However, it is not possible to tell if this is a precursor ofpolycystic ovary syndrome in a proportion of cases.
Tumours of the ovaries
Primary tumours of the ovary are divided into those derived from surface epithelium, those from sex- cord and stromal cells, and those from germ cells. Ii- addition to primary tumours, the ovary is frequentlyj involved in metastatic disease from other sitesi Malignant tumours of ovary spread locally and particularly seed to peritoneum, when ascités is ai important complication.
Epithelial tumours of the ovary can differentiat into several types.
tumours.
2. Tubal differentiation: serous ovarian tumours.
3. Endometrial differentiation: endometrioid and clear-cell ovarian tumours;
4. Transitional differentiation: Brenner tumours.
In histological assessment of epithelial tumours of the ovary, it can be difficult to decide which lesions are benign and which are malignant. In between those tumours that are obviously benign or malignant are some cases in which there are histological features of atypical cells and abnormal tissue architecture, but no evidence of invasion. Such lesions are termed tumours of borderline malignant potential>>. Most borderline tumours behave in a benign fashion, the remainder behaving as low-grade malignant tumours.
Serous tumours of the ovary contain watery fluid and are often bilateral.
Benign serous tumours of the ovary are termed <serous cystadenomasn. These thin-walled, unilocular cysts contain watery fluid and are bilateral in about 10% of cases. Microscopically, they are lined by a cuboidal, regular epithelium in which small papillary projections may be seen. A related tumour, termed an adenofibroma, is a benign, sometimes solid and sometimes cystic (cystadenofibroma) tumour, composed of benign serous epithelium and spindle- cell stroma. Malignant serous tumours of the ovary are teimed <<serous cystadenocarcinomas>>. These are the most common form of ovarian carcinoma and are bilateral in about half of all cases. Macroscopically, tumours may be cystic, mixed solid and cystic, or largely solid in appearance. Histologically they are composed of cystic cavities lined by columnar and cuboidal cells, with papillary proliferations of cells and solid areas. Cells are pleomorphic and mitoses are seen. Importantly, invasion of the ovarian stroma does occur, confirming the malignant character. These lesions are I associated with an overall 20% five-year survival.
Borderline serous tumours of the ovary are bilateral in about 30% of cases. Macroscopically,1 tumours may be cystic, or mixed solid and cystic. Histologically they are composed of cystic cavities lined by columnar and cuboidal cells, with papillary] proliferation of cells and solid areas. Cells are pleomorphic and mitoses are seen. However, invasion of the ovarian stroma does not occur, despite the presence of cellular atypia. These lesions are associated with an overall 75% ten-year survival.
